Almost all bacteria require iron for their survival and have evolved sophisticated iron acquisition systems to obtain this vital element from their environment. During infection many pathogens synthesize and secrete small molecule iron chelators known as siderophores that sequester iron from the host then transport the siderophore-iron complex back into the bacterium. The crucial role of siderophores for virulence has been demonstrated for several noted bacterial pathogens including Mycobacterium tuberculosis, Yersenia pestis, Vibrio cholera, Bacillus anthracis and Pseudomonas aeroginosa the causative agents respectively of tuberculosis, plague, cholera, anthrax, and opportunistic infections in patients with cystic fibrosis. All of these pathogens produce mixed-ligand siderophores that are biosynthesized by multifunctional proteins known as non-ribosomal peptide synthetases (NRPS) often in combination with polyketide synthases (PKSs).
Tuberculosis (TB) is the leading bacterial cause of infectious disease mortality. The current WHO-approved treatment for TB, known as directly observed therapy short-course (DOTS), involves a three- or four-drug regimen comprising isoniazid, rifampin, pyrazinamide, and/or ethambutol for a minimum of 6 months. While these first-line agents remain useful in treating susceptible Mycobacterium tuberculosis strains, the emergence of multi-drug resistant tuberculosis demands the development of new drugs. Currently, there is a need for therapeutic agents and methods that are useful for treating bacterial infections, including bacterial infections caused by pathogens that synthesize and secrete small molecule iron chelators.